DHEA is a naturally occurring steroid secreted by the adrenal cortex with apparent chemoprotective properties. Epidemiological research has shown that low endogenous levels of the natural steroid dehydroepiandrosterone (DHEA) correlate with increased risk of developing some forms of cancer, such as premenopausal breast cancer in women and bladder cancer in both sexes. R. D. Bulbrook et al., Lancet 2, 395-398 (1971); B. Zumoff, et al., Cancer Res. 41, 3360-3363 (1981); G. B. Gordon, Cancer Res. 51, 1366-1369 (1991); K. J. Helzlsouer, Cancer. Res. 52, 1-5 (1992). The ability of DHEA and DHEA analogs to inhibit carcinogenesis is believed to result from their uncompetitive inhibition of the activity of the enzyme glucose-6-phosphate dehydrogenase (G6PDH).
G6PHD is the rate limiting enzyme of the hexose monophosphate pathway, a major source of intracellular ribose-5-phosphate and NADPH. P. A. Marks et al., Proc. Nat. Acad. Sci. USA 46, 447-452 (1960). Ribose-5-phosphate is a necessary substrate for the synthesis of both ribo- and deoxyribonucleotides required for the synthesis of RNA and DNA. NADPH is a cofactor also involved in nucleic acid biosynthesis and the synthesis of hydroxmethylglutaryl Coenzyme A reductase (HMG CoA reductase). S. Schulz et al., Inhibition of Protein Isoprenylation and p21ras Membrane Association by DHEA in Human Colonic Adenocarcinoma Cells in Vitro, Cancer Res. (Dec. 15, 1991).
HMG CoA reductase is a very unusual enzyme in that it requires two moles of NADPH for each mole of product, mevalonate, produced. Thus, it appears that HMG CoA reductase would be ultrasensitive to DHEA-mediated NADPH depletion, and that DHEA-treated cells would rapidly show depletion of intracellular pools of mevalonate. Mevalonate is required for DNA synthesis, and DHEA arrests human cells in the G1 phase of the cell cycle in a manner closely resembling that of the direct HMG CoA reductase inhibitor lovastatin. S. Schulz et al, Mechanism of Cell Growth Inhibition and Cell Cycle Arrest in Human Colonic Adenocarcinoma Cells by DHEA: Role of Isoprenoid Biosynthesis, Cancer Res. (submitted). Because G6PDH produces mevalonic acid used in cellular processes such as protein isoprenylation and the synthesis of dolichol (a precursor for glycoprotein biosynthesis), DHEA inhibits carcinogenesis by depleting mevalonic acid and thereby inhibiting protein isoprenylation and glycoprotein synthesis.
Mevalonate is the central precursor for the synthesis of cholesterol, as well as for the synthesis of a variety of nonsterol compounds involved in posttranslational modification of proteins (farnesyl pyrophosphate and geranlygeranyl pyrophosphate); for dolichol, which is required for the synthesis of glycoproteins involved in cell-to-cell communication and cell structure; and for ubiquinone, an antioxidant with an established role in cellular respiration. P. Mitchell, Annals of the N.Y. Acad. Sci. 341, 564 (1980); M. Gutman, Biochem. Biophys. Acta. 594, 53 (1980).
Adequate ubiquinone is essential for maintaining proper cardiac function and the addition of exogenous ubiquinone has recently been shown to have beneficial effect in patients with chronic heart failure. S. Greenberg et al., J. Clin. Pharmacol. 30, 596-608 (1990); S. A. Mortensen et al., Int. J. Tiss. Reac. 12(3), 155-162 (1990). Additionally, ubiquinone has been shown to be depleted in humans and animals treated with the direct HMG CoA reductase inhibitor lovastatin. K. Folkers et al., Proc. Nat. Acad. Sci. USA 87, 8931-8934 (1990); R. A. Willis et al., Proc. Nat. Acad. Sci. USA 87, 8928-8930 (1990). Such lovastatin-induced depletion of ubiquinone has been shown to lead to chronic heart failure (or to upgrading of low heart failure into life-threatening high grade heart failure). K. Folkers et al., Proc. Nat. Acad. Sci. USA 87, 8931-8934 (1990).
DHEA, unlike lovastatin, inhibits HMG CoA reductase indirectly by inhibiting G6PDH and depleting NADPH, a required cofactor for HMG CoA reductase. However, DHEA indirectly inhibits HMG CoA reductase sufficiently to deplete intracellular mevalonate. S. Schulz et al., Inhibition of Protein Isoprenylation and p21ras Membrane Association by DHEA in Human Colonic Adenocarcinoma Cells in Vitro, Cancer Res. (Dec. 15, 1991). This, too, will lead to ubiquinone depletion and consequent chronic heart failure following long term usage.
Thus although DHEA was once considered a safe drug, it is now predicted that with long term administration of DHEA or its analogs, chronic heart failure occurs as a complicating side effect. Further, some analogs of DHEA produce this side effect to a greater extent in that specific analogs have been reported to be a more potent inhibitor of G6PDH than DHEA.